Description of Research Expertise

Research Interests
- Hepatic stellate cell and portal fibroblast function in liver fibrosis
- The role of mechanical factors and ECM proteins in myofibroblast differentiation in fibrosis
– Characterization of myofibroblast precursor populations in liver fibrosis
– The role of liver stiffness and other mechanical factors in fibrosis and cirrhosis
- The etiology and mechanism of fibrosis in biliary atresia
- The mechanism of fibrosis in autosomal recessive polycystic kidney disease
- The role of fibronectin splice variants in liver fibrosis and angiogenesis

Description of Research
My research focuses on the mechanism of hepatic fibrosis.

Liver fibrosis results from the deposition of excess, abnormal extracellular matrix by myofibroblasts derived from non-fibrogenic cells that undergo “activation” in the context of chronic liver injury. We are investigating the mechanism of fibrosis in three ways: a) by studying the matrix, mechanical, and soluble factors that influence activation of known myofibroblast precursor populations; b) by identifying new fibrogenic cell populations and new means of studying previously identified cells; and c) by applying the results of our experiments with isolated cells to whole animal models and to the study of human diseases.

We are studying the matrix, mechanical, and soluble factors that influence activation of two known myofibroblast precursor populations, hepatic stellate cells (HSC) and portal fibroblasts (PF). HSC have for many years been regarded as the most important myofibroblast precursor population and have been studied extensively in a cell culture model of activation. PF have only recently been identified and isolated but are now appreciated to be as important in some liver diseases as HSC. We have successfully developed and characterized an in vitro activation assay for PF. We have used a novel cell culture system to study the role of mechanical and chemical factors in activation of both PF and HSC and have demonstrated for the first time that activation of both PF and HSC is determined by matrix stiffness. Additionally, we have shown that PF absolutely require TGF-β for activation, while HSC require TGF-β, signaling specifically via the downstream mediator Smad3, only in late stages of activation. We have proposed different models of in vitro activation for each cell type.

We are also applying our findings about the role of mechanical stiffness in liver myofibroblast activation to whole animal models. We have demonstrated in rat models of fibrosis that increased liver stiffness precedes matrix deposition and that fibrosis and liver stiffness are not linearly related. Current work is focused on determining the cause of early increases in liver stiffness, in particular the role of collagen cross-linking enzymes, the relevance of in vivo liver stiffness to myofibroblast activation, the role of early matrix synthesis, and the role of TGF-β in the mechanical changes of the liver in fibrosis. We are also interested in the role of mechanical changes in driving the architectural changes of late fibrosis and cirrhosis.

We have recently begun studying other mechanical factors (including compressive pressure) which drive myofibroblast activation and fibrosis in the liver. Additionally, we are actively studying the role of fibronectin splice variants in fibrosis and angiogenesis, and the role of small proteoglycans (including lumican) in collagen mechanics and myofibroblast differentiation.

Human model diseases of interest to our studies of the mechanism of fibrosis include biliary atresia and autosomal recessive polycystic kidney disease (ARPKD). We are part of an international group which has recently identified a plant toxin that causes biliary atresia and are actively studying its effects on cholangiocytes. We area also studying the mechanism of fibrosis in ARPKD, in particular the role of portal fibroblasts and mechanisms of portal hypertension in this disease.

Summary: Overall, my goal is to develop a unified and comprehensive model of liver fibrosis that incorporates multiple cell types, soluble and secreted factors, matrix proteins, and local and regional mechanical factors.